Preparation of salts of carboxylic acids containing a beta-lactam groups

ABSTRACT

A process for the preparation of salts of carboxylic acids containing a beta-lactam group, namely penicillins, cephalosporins and 6-amino penicillanic acid. The process uses very mild conditions and the salts are obtained directly in dry form. Risk of hydrolysis or decomposition of the sensitive salts during preparation, isolation and drying of the salts is minimized by the process of the invention. The salts are obtained in good yields and high degree of purity.

United States Patent Kiesewetter et al.

[ Dec. 16, 1975 Appl. No.: 147,677

US. CL... 260/239.1; 260/243 C; 260/3067 C; 260/306.7 E; 424/271;424/246 Int. Ci. C07D 499/16 Field of Search 260/243 C, 306.7 C, 239.1,260/3067 E References Cited UNITED STATES PATENTS 3/1970 Weissenburgeret a1 260/243 C 3,509,168 4/1970 Christman et al. 260/2391 3,575,9704/1971 Weissenburger et a1 260/243 C 3,654,266 4/1972 Robinson 260/23913,669,957 6/1972 Robinson et a] .4 260/2391 Primary ExaminerNicholas S.Rizzo Attorney, Agent, or FirmWeiser, Stapler & Spivak ABSIRACT Aprocess for the preparation of salts of carboxylic acids containing abeta-lactam group, namely penicillins, cephalosporins and 6-aminopenicillanic acid. The process uses very mild conditions and the saltsare obtained directly in dry form. Risk of hydrolysis or decompositionof the sensitive salts during preparation,-

isolation and drying of the salts is minimized by the process of theinvention. The salts are obtained in good yields and high degree ofpurity.

29 Claims, N0 Drawings 1 PREPARATION OF SALTS OF CARBOXYLIC ACIDSCONTAINING A BETA-LACTAM GROUP The invention concerns a process forthemanufacture of salts of carboxylic acids containing a beta-lactam ringand in particular, for a process for the manufacture of pharmaceuticallyacceptable alkalior alkaline earth salts of such carboxylic acids. Thebeta-lactam ring-containing carboxylic acids of the invention arepenicillins, cephalosporins, as well as 6- aminopenicillanic acid,sometimes referred to herein as APA for convenience.

The process of the invention comprises reacting a silyl derivative of apenicillin, a cephalosporin or of 6-aminopenicillanic acid,respectively, (in which silyl derivative at least the carboxylic groupof the betalactam-containing carboxylic acid is linked with the siliciumatom of a silyl group derived from a trialkylor triaryl silanol or froma dialkylor diaryl silandiol), with a salt of a carboxylic acid or witha O-metal derivative of an alcohol, of a phenol, of a trialkylsilanol orof a triarylsilanol in presence of an organic aprotonic solvent whichare free of water or alcohol, hereinafter referred to as anhydrous,non-hydroxylic solvent, or which contains at the most an amount of wateror alcohol insufficient for desilylation of said silyl derivative.

The process of the invention is the first process for preparing a saltof any carboxylic acid, in which the carboxylic group in the startingmaterial is not in free form or in form of a salt, but is in the form ofan ester. The products obtained by the process especially the calciumsalts are an embodiment of the invention.

Alkali-, and alkaline-earth, and other salts of these compounds areknown. Their manufacture has taken place essentially in the followingmanner. A solution of the carboxylic acid containing a beta-lactam ringcan be neutralized in organic or aqueous-organic solvents by means of analkali solution, an amine, or a salt of a weak acid with thecorresponding bases or metallic alcoholates, and so forth. The isolationof the salts is carried out depending on the solubility and stability ofthe products, by concentration of the solution, evaporation and/orfiltration of the precipitated crystals, in some cases also byfiltration of the products precipitated by the addition of solvents inwhich the desired salts are insoluble or difficultly soluble. Anotherknown method discloses a double reaction of amine salts of carboxylicacids containing a beta-lactam ring soluble in organic solvents withmetallic salts of certain fatty acids, such as those ofalpha-ethylhexanoic acid, or even also with alcoholates and others insuitable solvents, such as chlorinated hydrocarbons, acetone, butylacetate, and so on.

The first described process is especially well suited for penicillins orcephalosporins which are soluble in organic solvents as the free acids.However, it is necessary in that case, if with metallic salts ofinorganic or organic acids are used, that the antibiotic used bedistinctly more acid than the acid component of the salt used.Especially, the use of organic solvents containing water, frequentlycause difficulties during the isolation of the salts of the antibiotics,particularly if these products are hygroscopic and/or relativelyunstable as, for example, especially the salts of6-(alphaaminoacylamido)-penicillanic acids. With the second describedprocess 6-(alpha-aminoacylamido)penicillanic acids also may, undercertain conditions, be employed since some amine salts of thesecompounds (in contrast to the free penicillins, their alkali salts, andlike others) are, for example, relatively readily soluble in chlorinatedhydrocarbons; therefore, the products may be separated as a solid fromsuch solutions after the reaction. But this process requires the makingof the necessary amine salts, as intermediate product, and this ishowever, very frequently accompanied with losses of material.

By other attempts to isolate, for example, alkali salts of6-(alpha-aminoacylamido)-penicillanic acids from their solutions, forexample, by freeze-drying or by other gentle drying procedures, arelatively extensive decomposition occurs. See, for example, BritishPat. No. 903,785, and the introductory part of German Pat. DisclosureNo. 1,197,460. Hence, various proposals are already known for makingalkali salts, especially those of alpha-aminobenzyl penicillin in such away that alpha-aminobenzyl penicillin is converted into the salt of anorganic base, as for example, of triethylamine or of diethylamine. Thesalt is dissolved in a chlorinated hydrocarbon, especially methylenechloride, and then the alkali salt of the alpha-aminobenzyl penicillinis precipitated from this solution by the addition of an alkali metalsalt, such as of 2-ethylcaproic acid, or an alkali alcoholate, such assodium isopropylate. Especially, the sodium salts of alpha-aminobenzylpenicillin, however, cannot be obtained in optimal purity and yield,according to the known aforesaid, multiple-step process. Losses in yieldand/or impurities occur, particularly also during the manufacture of thesalts.

It is to be noted that in accordance with all known process for themanufacture of salts, especially of the alkalior earth alkaline salts ofcarboxylic acids containing a beta-lactam ring, the carboxyl group whichis capable of the salt formation is present in the corresponding initialsolution free, or bound in as an amine salt.

The process of the invention distinguishes itself fundamentally from theart in that the carboxyl group of the carboxylic acids containing thebeta-lactam ring is not present in the free form nor as the salt in theinitial product used for the salt formation. In contrast, the carboxylgroup is present as an ester, derived from a trialkylor triarylsilanol,or from a dialkylor diarylsilandiol. The preparation of such silylderivatives of carboxylic acids containing a beta-lactam ring, in whichat least the carboxyl group is esterified with one of the groups named,(and which may be designated as a silyl ester) is known.

Typical of the pertinent literature on this subject, the following maybe mentioned, which are incorporated herein by reference. Concerning themanufacture of silylated penicillins, or cephalosporins frompenicillins, respectively, cephalosporins, reference is made to BelgianPat. No. 718,824, Dutch Pat. Disclosures Nos. 6606,872, 67.l3,809,67.10,835, US. Pat. No. 2,746,956. Concerning the manufacture ofsilylated 6-aminopenicillanic acid and its conversion into silylatedpenicillins reference is made to Belgian Pat. Nos. 615,344, 615,401.653,862, British Pat. Nos. 959,853, 964,449, 1,008,468, German Pat. No.1,159,449, German Pat. Disclosures Nos. 1,800,698, 1,814,085; 1,912,904;1,923,624; 1,931,097; 1,932,351; Dutch Pat. Disclosures Nos: 64.01,841;6611,888', 68.00768, 68.18057, Swedish Pat. Disclosures No.

3 10.179. Swiss Pat. Disclosure Nos. 446,336, and US. Pat. No.3.479,338. For the manufacture of silylated 7-aminocephalosporanic acidsand their conversion into silylated cephalosporins reference is made toBelgian Pat. Disclosures Nos. 737,761. British Pat. Disclosure No.1,073,530, Dutch Pat. Disclosure No. 67.l7,107 and 68.18868. Referenceis also made to the article on PENlClLLlN in The Pharmacological Basisof Theurapeutics, Goodman and Gilman (3rd Ed.); The MacMillan Company,New York, 1968, pages l 193 to 1229, especially page 1208, the chapteron Semisynthetic Penicillins. their Pharmacology and AntimicrobialProperties. All these references are incorporated herein by reference.

From the state of the art it is known that the silyl derivatives ofcarboxylic acids containing a betalactam ring can be hydrolyzed oralcoholyzed by water or alcohol. respectively. or other proton-activecompounds with formation of the free acids. For the manufacture of saltsof carboxylic acids containing a betalactam ring, the approach hashitherto always been to make the free carboxylic acid from the silylesters of said acids by hydrolysis or alcoholysis, and so on, and

the free carboxylic acid was then converted in a known 7 manner (such asdisclosed above) into the salts. In case the amino group is present as asalt in the silyl derivative of a 6-(aminoacylamido)-penicillanic acid,as is described in US. Pat. No. 3,479,338. a treatment with a base isrequired before or after desilylation.

Surprisingly, it has now been found that salts of carboxylic acidscontaining a beta-lactam ring can also be obtained from their silylderivatives without the intermediary splitting of the silyl ester group,respectively, without the manufacture of the free acid. This object isachieved by bringing into reaction a solution of the silylated lactamring-containing carboxylic acid in an aprotic, organic. anhydroussolvent with a solution of a salt of an organic acid, of a metalalcoholate, or of phenolates, or of a metal trialkylortriarylsilanolates. The solution should be anhydrous, and non-hydroxylicor merely containing such an amount of water or alcohol that isinsufficient to desilylate the silyl derivative of the carboxylic acidcontaining a beta-lactam ring.

In accordance with the invention, there is used a silyl derivative of acarboxylic acid containing a beta-lactam ring, preferably a derivativeof a 6-acylaminopenicillanic acid, especially of a compound of thestructure wherein X is an acyl residue, especially the residue of analpha-phenoxyacetie, propionic-, or butyric acid, of an alpha-amino,alpha-halogeno-, or of an alpha-alkoxyphenylacetic acid. of a 3-(or-)aryl-5-(or 3-)a1- kylisoxazolyl-4-carboxylic acid, of al-aminocyclohexan-l-carboxylic acid, or of l-amino-cycloalkanecarboxylic acid, the cycloalkane being of 4 to 8 carbon atoms, forinstance, and further such acyl residues of acids as are known. forinstance, as disclosed by Baer and Zamack in Die Pharmazie pages l0- 14(1970) which is incorporated herein by reference also including theresidue of such as acids as used in acylating beta-lactam ringcarboxylic acid. including cephalosporins, including furthermore acylresidue of alphaaminocyclodiene acetic acid. amino-thionyl,alphaamino-thionyl-, alpha-aminophenyl-. alpha- (guanylureido)phenyl,alpha-sulfonyl methyl amido-, alpha-methylene amino-. phenyl-carboxyphenyl-. alpha-carboxy thienyl acetic acids, Y is a group derived from atrialkylor triarylsilanol. or from a dialkyl or diarylsilandiol and islinked with a silicium atom. and Z is a hydrogen atom or the same groupas Y.

The silyl derivatives of a carboxylic acid containing a beta-lactam ringwhich are preferred are those in which at least the carboxyl group islinked to a group S| of the structure wherein R R and R are an alkyloran aryl residue and, preferably, are each an alkyl residue of up to 3carbon atoms. in particular, each a methyl group, and when aryl, an arylhaving 6 to 12 carbon atoms in the ring. preferably 6, like phenyl. Ofthe group of such silyl derivatives of carboxylic acids containing abetalactam ring, which are derived from a dialkyl or diaryl-silanediol,there are preferred those which are derived from a lower dialkyl silanediol (alkyl of l to 6 carbons). especially from a dimethyl silane diol.

The process according to the invention, may be illustrated by the use ofa trimethyl silyl ester of a carboxylic acid containing a beta-lactamring by the following reaction (I) wherein R is the residue of acarboxylic acid containing a beta-lactam ring, R is an acyl residue, analkylor an aryl residue or a group of the structure wherein R to R arealkylor aryl residues and Cat is a cation.

When in accordance with the process of the invention, there is used asilyl derivative of a 6- (aminoacylamido)-penicillanic acid with asalt-like bound amino group (compare, for example, structure I of GermanPat. Disclosure, No. 1 800 698), the amino group should be convertedfirst into the free or silylated compound before the manufacture of, forexample, the alkali salt of this 6-(aminoacylamido)-penicillanic acid.This can be performed by example, according to the process known fromthe US. Pat. No. 3,479,338.

As 6-(aminoacylamido)-penicillanic acid, the6-(alpha-aminoacylamido)-penicillanic acids (in the form of theirracemate, also in the optically active form), are especially worthy ofconsideration.

When in accordance with the invention, a silyl derivative of acarboxylic acid containing a beta-lactam ring of the aforesaiddesignated type is reacted with a solution of a compound of the formulaR -O-Cat, which solution contains wateror alcohol in an amountinsufficient for the desilylation of the silyl derivative of thecarboxylic acid containing a beta-lactam ring, the desired salt of thecarboxylic acid containing a beta-lacor the silyl ester of the organicacid, or the silyl ether of the alcohol or phenol which was present inthe alcoholate or phenolate. With regard to the course of the reaction,it is assumed that the amount of water present (for example)quantatively splits off the corresponding amount of the silyl-group (asis equivalent to the aforementioned amount of water) from the silylderivative of the carboxylic acid containing the beta-lactam ring, andforms, for example, the disiloxane. Insofar as the carboxyl group of thebeta-lactam ring-containing carboxylic acid is thereby also liberated,it is possible then to react it with the saltof the organic acid withliberation of the organic acid and formation of the salt of thebeta-lactam ring-containing carboxylic acid. It is not yet entirelyclear whether, thereafter the liberated carboxylic acid splits on itsown accord whatever silyl derivatives of the beta-lactam ring-containingcarboxylic acid which may still be present. and thereby converts itselfinto its silyl ester, or whether then, as in absolutely anhydrous oralcoholfree solution, a direct interaction takes place between the silylderivative of the carboxylic acid containing the beta-lactam ring andthe salt of the organic acid (or metal alcoholate). But thisconsideration does not affect the success of the reaction.

It is possible to describe this variant of the process of the invention,under consideration of the aforesaid explanations in the form of areaction equation as follows. There is used as example, atrimethyl-silyl-ester of the beta-lactam ring-containing carboxylic acidwhich is reacted with an equimolar amount of the compound of the formulaR -O-Cat and one-fourth of the amount of water which would be requiredfor the complete desilylation of the silyl derivative of the beta-lactamring-containing carboxylic acid. The reaction can be represented asfollows In the formula, R, R and Cat have the same definition as'statedabove.

Typical compounds of the formula R -O-Cat are by way of example, thesodium-, potassium-, calcium-, magnesium-, triethylamine-, etc.- saltsof carboxylic acids'which contain with the exception of one or severalcarboxyl groups no other proton-active groups. Examples for such acidsare butyric acid, isobutyric acid, alpha-ethylbutyric acid,isoamylethylacetic acid, dialkylmalonic acids (with a lower alkylpreferably), phenylacetic acid, or, especially, alpha-ethylhexanoicacid. While triethylamine has been mentioned, other alkyl amines aresuitable too. Furthermore, the compounds of the formula R -O-Cat can bethe potassiumor sodium salts of a lower aliphatic alcohol (asisopropanol, ter.butanol), of a phenol, or of a trialkyl-, (loweralkyl), especially of trimethylsilanol or of triphenylsilanol. Amongstthe acids mentioned above fatty acids (as of 4 to carbon atoms) form adesirable group and dialkyl (preferably lower alkyl) dicarboxylic acidslike dimethyl malonic acid. Amongst the 6 aliphatic dicarboxylic acids,malonic, succinic and glutaric have been considered, expecially thedi-lower alkyl dicarboxylic acids.

The silyl derivative of the beta-lactam ring-containing carboxylic acidsare readily soluble in anhydrous, aprotic solutions. Likewise, theby-products formed in the reaction are equally soluble as the silylderivatives of beta-lactam ring-containing carboxylic acids in thevarious aprotic solvents and are, therefore. readily separable from thedesired salts formed in the process, these salts being generally verydifficultly soluble in aprotic solvents.

The fact that the process of the invention actually takes the coursedescribed in equation (I) could be demonstrated by reacting thetrimethylsilyl ester of a penicillin with an anhydrous solution of thesodium salt of the alpha-ethylhexanoic acid in absolute ether. Thesolution of the sodium salt of alpha-hexanoic acid was obtained ascompletely anhydrous by adding somewhat more ofN-methyl-N-trimethylsilylacetamide than'the necessary equivalent to theamount of water contained in it as derived from its manufacture, andtherewith converting the water into hexamethyldisiloxane. After thereaction is completed the sodium salt of penicillin was separated andthe remaining solution was examined by gas chromatography. Thereby, itwas seen that this solution contained the trimethylsilyl ester ofalphaethylhexanoic acid, in addition to the N-methylacetamide andhexamethyldisiloxane, which came from the drying of the solution ofsodium-ethylhexanoate, and a small amount of excessN-methyl-N-trimethylsilylacetamide.

The solution of the silylated carboxylic acid containing a beta-lactamring should be as free as possible of salts which could have been formedin the manufacture of the silyl compound. By way of example, aminesalts, such as triethylaminoor pyridine hydrochloride are noticablysoluble in chlorinated hydrocarbons and other solvents. If necessary. itis possible to remove from the solution of the silyl derivatives ofbeta-lactam ring-containing carboxylic acids any undesirable saltscontained therein, by treatment with suitable solvents, such as ether,petroleum ether, benzene, etc. in which these salts are insoluble but inwhich silyl derivatives are readily soluble. The salts can be removed byfiltration. The obtained salt-free solution of the silyl derivative ofthe carboxylic acid containing the beta-lactam ring can them be employedfor the reaction, according to the invention.

Typical solvents which can be used in the invention are those which arefree of a proton active group and thus are inactive with respect to thesilyl derivative which they cannot desilylate and cannot split off thecation in the formula R -O-Cat. Illustrative of such solvents areacyclic ethers, cyclic ethers, aliphatic saturated hydrocarbons,aromatic hydrocarbons. also halogenated hydrocarbons, esters ofcarboxylic acids, nitriles, amides, petroleum ethers and like solvents.

Typical ethers that can be used are the following: dialkyl etherswherein the alkyl group may have for instance up to 6 carbon atoms suchas di-isobutyl ether, methylisopropyl ether, methylisoamyl ether,n-propyl isopropyl ether, or such ethers as ethylene glycol dimethylether, ethylene glycol diethyl ether, propylene glycol dimethyl ether,methyl phenyl ether, tetrahydrofuran, or dioxane, or such saturated orhalogenated or other aromatic hydrocarbons such as pentane, octane.petroleum ether, methylcyclohexane, decaline, methylene chloride,toluene, xylene, chloroform. tetrachloro hydrocarbons, or such esters ofcarboxylic acid as methylformate. ethylformate, ethylacetate, propylacetate. isopropyl acetate, methoxyethylacetate, methoxyacidic acidethyl ester. alpha-methoxy propionic acid ethyl ester. beta-acetoxypropionic methyl ester, benzoic methyl ester, tetrahydro benzoic ethylester; or other solvents as nitriles and amides such as acetonitrile,formamide, benzonitrile. N-methylformamide, dimethylformamide,acetamide, methoxy acidic acid dimethylamide, and such further solventsas dimethylsulfide, diethylsulfide, thiophene. and other such solvents.

The process of the invention is performed preferably at a temperature atwhich the reaction goes to completion within the time desired, forexample between about the freezing point of the liquids, the solvent ifone is used, to the boiling point of the reaction mixture. As anoperative range 50C to 50C. preferably C to about 35C and preferablyabout to C. may be indicated.

According to the invention. the salt of a beta-lactam ring-containingcarboxylic acid is suitable made as follows. A solution (A) of thecarboxylic acid salt (or a solution, for example, of analkali-isopropylate or tert. butylate. an alkaliphenolate or analkalitrimethylor triphenylsilanolate) is mixed with agitation andexcluding moisture with the (anhydrous and, as much as possible, alsosalt-free) solution (B) of an equivalent amount of the silylatedcarboxylic acid containing a beta-lactam ring. Solution A may be addedto solution B, or vice-versa. Solution (A) should be anhydrous andalcohol-free or, contain at most an amount of water or alcoholinsufficient to desilylate the silyl derivative of the beta-lactamring-containing carboxylic acid present in solution B.

In accordance with the invention, the reactants are used in asubstantially equimolar amount; if desired there may be used althoughthis is not necessary an excess of the reactant R,-O-Cat; for instance1.0 to 1.1 is a satisfactory range. If desired the silyl derivative ofthe carboxylic acid may be used in excess.

The salt of the beta-lactam ring-containing carboxylic acid separatesgenerally spontaneously. Filtration (under exclusion of air moisture)and rewashing with absolute ether yields the salt in a very high degreeof purity, especially, if the process has used as starting material themonosilyl derivative of the beta-lactam ring-containing carboxylic acidin which the carboxyl group is silylated (esterified).

Should the silyl derivative of the beta-lactam ringcontaining carboxylicacid contain more than one silyl group, it is recommended to use asolution A which contains an amount of water or alcohol insufficient fordesilylation, and/or to carry out the rewashing with a solvent which wasnot extremely dry, whereby the disilylation of the silyl derivative ofthe beta-lactam ring-containing carboxylic acid, which is alreadyprecipitated as salt is completed by the small amount of water whichthen come into reaction.

The preparation of an absolutely anhydrous solution of a carboxylic acidsalt of the formula R O-Cat may be carried out in such a way that acarboxylic acid as, for example, alpha-ethylhexanoic acid is dissolvedin absolute tetrahydrofuran. an equivalent amount of a base (forexample. solid sodium hydroxide or potassium hydroxide. calcium oxide,magnesium oxide. triethylamine, etc.) is added and, after the solidportion is dissolved, and anhydrous sodium sulfate is added in order toremove the greatest part of the water formed by the neutralization. Theproduct is filtered and the water-containing drying agent is washed withtetrahydrofuran. This step can, of course, be omitted in the use ofamines since no water forms during their neutralization. Uponconcentration of the solution by evaporation. the residue is dissolvedin a suitable aprotic solvent, respectively mixture of solvents. Forexample. there can be used a mixture made up of tetrahydrofuran/ ether,in a ratio of 1:20, and the water content is then determined from analiquot part of this solution. Finally, there is added an amount of thesilylating agent equivalent to the water contant which has beendetermined, especially, trimethylsilylacetamide orN-methyl-N-trimethylsilylacetamide. The resulting solution can then beemployed for the process, according to the invention, without having theacetamide, the N-methylacetamide as well as the hexamethyl-disiloxanefrom the drying step influence the reaction.

The salts of the invention are generally white solids, which areobtained or can be reduced to powdery form.

The success of the process of the invention, was not anticipated in viewof the art for making salts of carboxylic acids which exist in the formof their silyl esters. It was necessary first to free the carboxyl groupby hydrolysis or alcoholysis and only then the free carboxyl group couldbe converted into its salt in a manner known. One skilled in the art,therefore, had to recognize that particularly even in the presence of anamount of water or alcohol insufficient for desilylation, salt formationcan at any rate be achieved only to the ex tent that the beta-lactamring-containing carboxylic acid is liberated from its silyl ester.Surprisingly, however, the yields of salts of the beta-lactamring-contain ing carboxylic acids in accordance with the invention arefar higher than the maximum yields that can be expected in the light ofthe above.

The process according to the invention contributes significantly to theart. It provides the manufacture and isolation of salts of beta-lactamring-containing carboxylic acids under notably mild conditions, wherebyfurthermore the salts are directly obtained in a dry form and, whereby,the risk of hydrolysisor decomposition is avoided during themanufacture, isolation, and the removal of bound water of residue, whichis a step necessary with the processes known. The salts of the processaccording to the invention are always obtained in a high degree ofpurity and yields. This is all the more surprising that according to theinvention it is the first method (also independently from the field ofthe betalactam ring-containing carboxylic acids) in which a salt is madefrom the ester of a carboxylic acid without there taking place anintermediate saponification of the ester to the free acid.

The following non-limiting examples further illustrate the invention.

EXAMPLE 1 3.5 g of Penicillin V (free acid) was suspended in 30 ml ofabsolute ether and then 1.75 g N-methyl-N-trimethylsilylacetamide wasadded; a clear solution resulted. After one hour, this solution waspoured into an anhydrous solution of 0.01 mole of a sodium salt ofZ-ethylhexanoic acid in a mixture of 5 ml tetrahydrofuran and 35 mlether (which had been made anhydrous by the addition of an amount ofN-methyl-N-trimethylsilylacetamide. corresponding to the water contentdetermined according to Karl-Fishcer method). Spontaneously, aprecipitate is formed which consisted of the sodium salt of penicillinV. The precipitate was sucked off, excluding moisture and was washedwith absolute ether. Thus there was obtained, after drying under vacuum,3.8 g or 102% of theory of product, penicillin content was 97%,determined iodometrically.

EXAMPLE 2 4.32 g (0.02 mole) of 6-aminopenicillanic acid (APA) wassuspended in 50 ml of absolute tetrahydrafuran and was converted to thedisilyl derivative of 6-aminopenicillanic acid by the addition of 5.6 mlof triethylamine and 5.2 ml of trimethylchlorosilane. After the additionof another 2.8 ml of triethylamine, the reaction mixture was treatedwith 3.4 phenoxyacetic acid chloride. It is then allowed to reactfurther for some time and the triethylamine hydrochloride is sucked offexcluding moisture; the triethylamine hydrochloride is then washed 3times, each with 30 ml of absolute tetrahydrofuran. The combined clearfiltrates are concentrated under vacuum to a volume of about 50 mlyielding Solution 1.

From 3.5 g of the sodium salt of Z-ethylhexanoic acid, 5 ml of absolutetetrahydrofuran, and 95 ml of absolute ether, a solution is prepared anda corresponding amount of -N-methyl-N-trimethylsilylacetamide is added,the water content being determined according to the Karl-Fischer method.Thus, Solution II is obtained.

Solution 1 is combined with Solution ll with good agitation, at whichtime the precipitation of the sodium salt of penicillin V beginsimmediately. After one hour it is sucked off, washed with ether, anddried in vacuum. The yield is 5.2 g or 80% of theory, by iodometricallydetermined assay the penicillin content is 96%.

Additional amounts of the product in a somewhat less pure form areobtained upon treatment of the mother liquor with ether, namely, 1.5 gby iodometrically determined assay the penicillin content is 91% oftheory.

EXAMPLE 3 a. 5.1 g of APA was converted into the disilyl derivative in asolution of 50 ml anhydrous ethyl acetate, (free of alcohol and ofacetic acid), in a known manner, by treatment with 6.5 ml triethylamineand 5.9 ml trimethylchlorosilane. The reaction mixture was treated with2.8 ml of quinoline and, subsequently, with 4.6 g alpha-phenoxybutyricacid chloride. It was then further agitated for another hour, thenfiltered under strict exclusion of moisture, and the residue was washed3 times, each with ml of absolute acetic acid ethyl ester. The combinedfiltrates were concentrated by evaporation under vacuum to about 125 ml.

b. 0.02 Mole of the sodium salt of 2-ethylhexanoic acid is dissolved ina mixture of 5 ml of absolute tetrahydrofuran and 45 ml of absoluteether, and upon determination of the water content it is made anhydrousby addition of an equivalent amount of N-methyl-N-trimethylsilylacetamide. The resulting solution is added to the solutionobtained in section (a) and is then treated under agitation with 220 mlof absolute petroleum ether. The reaction mixture is cooled and isallowed to stand for several hours. The precipitate is the sodium saltof 6-(alpha-phenoxybutyramido)-penicillanicacid. The product is suckedoff, washed with ether, and dried in vacuum. The yield is 7.2 g or 90%of theory; the penicillin content determined iodometrically is 90% oftheory.

EXAMPLE 4 A solution is prepared according to Example 3(a) and istreated with a solution of the potassium salt of 2-ethylhexanoic acid intetrahydrofuran. This latter solution was prepared from 1.23 g ofpotassium hydroxide and 3.17 g of 2-ethylhexanoic acid intetrahydrofuran and was made anhydrous after pre-drying with sodiumsulfate, by treatment with N-methyl-N- trimethylsilyl-acetamide. Thereaction mixture is treated under agitation with 200 ml absolutepetroleum ether and is then cooled. The precipitate crystallized outupon standing, is sucked off, washed with ether, and dried in thevacuum. The resulting potassium salt of6-(alphaphenoxybutyramide)-penicillanic acid is obtained in a yield of7.8 g or 93.5% of theory. The penicillin content determinediodometrically is 97% of theory.

EXAMPLE 5 10.8 g. (0.05 mole of APA) is suspended in ml absolutetetrahydrofuran and is converted. in known manner to the disilylderivative of APA by treatment with 14 ml of triethylamine and 13 ml oftrimethylchlorosilane. The deposited precipitate of triethylaminohydrochloride is removed by filtration under strict exclusion ofmoisture and washed twice, each with 40 ml of absolute tetrahydrofuran.The combined filtrates are concentrated to about 40 ml in the vacuumyielding Solution I.

A solution was prepared from 2.2 g of sodium hydroxide, 7.9 g of2-ethylhexanoic acid, and 30 ml of absolute tetrahydrofuran, which wasboiled down in vacuum subsequent to drying with anhydrous sodiumsulfate. The residue was dissolved in a mixture of 10 ml tetrahydrofuranand ml absolute ether. The water content was determined as 0.7 mg/ml,according to Karl-Fischer. For removal of the water the solution wastreated with 1.45 g N-methyl-N-trimethylsilylacetamide and then combinedwith solution I. A precipitate occurred spontaneously and after 30minutes it was sucked off under exclusion of moisture. The residue waswashed with ether (undried, commercial) and then dried in vacuum. Thesodium salt of APA was obtained in a yield of 12.1 g or 101% of thetheory. APA content determined iodometrically was 89 EXAMPLE 6 Asolution of 0.005 mole of the silyl derivative of7-(thienyl-2'-acetamido)-cephalosporanic acid in 50 ml absolute etherwas treated portion-wise with a solution of 0.9 g of the sodium salt ofZ-ethylhexanoic acid in a mixture of 1 ml of tetrahydrofuran and 20 mlof absolute ether, to which the amount of bis-trimethylsilylacetamidehad been added which corresponded to any water traces to be removed.(The silyl derivative of the cephalosporanic acid used was obtained froma salt of the cephalosporin by treating with 0.5 ml ofbistrimethylsilylacetamide and 0.65 ml of trimethylchlorosilane andsubsequent filtration.) The reaction mixture was cooled, then was suckedoff after several hours under strict exclusion of moisture, and washedwith absolute ether. Upon drying 1.4 g or 70 of theory of the sodiumsalt of 7-(thienyl-2'-acetamido)- cephalosporanic acid was obtainedwhich was proved to be identical with a sample of the authenticmaterial.

EXAMPLE 7 a. 7 g of penicillin V (free acid) was treated with 2.07 gbis-trimethylsilylacetamide and then made up with absolute petroleumether to a volume of 50 ml yielding Solution 1.

b. 21,5 ml of a solution of 0.01 mole of the calcium salt of2-ethylhexanoic acid (obtained by the reaction of calcium oxide with 2mole 2-ethylhexanoic acid in absolute tetrahydrofuran and subsequentdrying with sodium sulfate) is treated with 1 ml of N-methyl-N-trimethylsilylacetamide for removal of residual water. The resultingsolution is added to Solution 1 whereby a precipitate came downspontaneously, which becomes crystalline when storing the reactionmixture under cooling. The precipitate is sucked off, washed withabsolute ether, then with absolute petroleum ether, and finally dried invacuum. The calcium salt of penicillin V is obtained in a yield of 7.7 gor 104 7c of theory; iodometrically assay: 89 7%.

EXAMPLE 8 200 ml of absolute tetrahydrofuran is poured over about 3 g ofsodium wire and then a solution of 0.1 mole of phenol in 100 ml ofabsolute tetrahydrofuran is added dropwise under agitation. After theevolution of hydrogen ceases. the solution is filtered and concentratedby evaporation under vacuum. 2.32 g of the residue is dissolved in 10 mlabsolute tetrahydrofuran and treated with 1 mlN-methyl-Ntrimethylsilylacetamide. The resulting solution is added to asolution made according to Example 7(a) and the precipitate which isformed is sucked off after 2 hours. It is washed with absolute ether anddried in the vacuum. The resulting sodium salt of penicillin V isobtained in a yield of 7.0 g or 94 7c of theory; penicillin content byiodometrically assay was 95 7c.

EXAMPLE 9 200 ml of absolute tetrahydrofuran is poured over about 3 gsodium wire and a solution of 0.1 mole triphenylsilanol in 100 mlabsolute tetrahydrofuran is then added dropwise. When hydrogen gasceases form ing the solution is filtered and the filtrate isconcentrated to dryness by evaporation in vacuum. 7.2 g of the residueof sodium-triphenylsilanolate is dissolved in 25 ml absolutetetrahydrofuran and then 20 ml of absolute ether is added.

7 g penicillin V (free acid) is suspended in a mixture of 30 ml ofabsolute ether and 30 ml of absolute petroleum ether. A clear solutionis obtained by the addition of g N-methyl-N-trimethylsilylacetamide,which after one hour at room temperature is treated with the solution ofsodium triphenylsilanolate. The spontaneous formation of a precipitateoccurs which is sucked off. washed three times with 50 ml absolute etherand then is dried in vacuum at 60C The yield of penicillin V sodium saltis 7.5 g or 100% of the theory; by iodometrically assay the penicillincontent is 94%.

EXAMPLE 10 a. 21.6 g (0.10 mole) of APA is converted into the silylderivative of APA in the presence of absolute tetrahydrofuran, with 0.2mole of triethylamine and 0.2 mole of trimethylchlorosilane. asdescribed in Example 2. The triethylamine hydrochloride formed isfiltered off under strict exclusion of moisture and the filtrate is thenmade up to 500 ml with absolute tetrahydrofuran.

b. ml of the solution obtained according to Example l0(a), is cooled to-5C, is then treated with 2.8 ml triethylamine and thereafter slowlywith 3.09 g of phenyl-acetyl chloride. The reaction mixture issubsequently agitated for one more hour and then the triethylaminehydrochloride formed is filtered off again in the absence of airmoisture, yielding a filtrate designated as Solution 1.

3.52 g of the sodium salt of Z-ethylhexanoic acid is dissolved in amixture of 5 ml of absolute tetrahydrofuran and 35 ml of absolute ether.in a control experi ment it had been ascertained that this solutionstill contains mg water. The resulting solution was then added toSolution I and the mixture was allowed to stand 3 hours. The precipitateformed thereby was sucked off, washed 3 times, each with 50 ml ether.and dried in vacuum. The yield of penicillin G sodium is 5.9 g or 83% oftheory, with an iodometrically determined purity of 100% EXAMPLE 1 l Asolution is prepared by treating calcium oxide with 2 moles ofethylhexanoic acid in the presence of absolute tetrahydrofuran. which(after drying over anhydrous sodium sulfate and washing with absolutetetrahydrofuran) contains in 21.5 ml, 0.01 mole of the calcium salt of2-ethylhexanoic acid (21.5 ml of this solution still contains 23 mgwater).

21.5 ml of the solution prepared as aforesaid. is treated with 100 ml ofa solution obtained according to Example 10(a). A precipitate appearsspontaneously which is dried under suction after one hour. washed 3times, each with 30 ml of ether, and then dried in vacuum. The calciumsalt of APA is obtained in a yield of 4.9 g of 101.8% of theory, with aniodometrically determined purity of 92 7c.

EXAMPLE l2 7 g of penicillin V (free acid) is treated with 2.07 g ofbis-trimethylsilylacetamide and then with absolute petroleum ether untilthe resulting solution has a volume of 50 ml. This solution is thenmixed with 21.5 ml of a solution of 0.01 mole of the calcium salt ofethylhexanoic acid, prepared as described in Example 11. A spontaneousformation of a precipitate occurs. The reaction mixture is allowed tostand for some time under cooling. The precipitate is then sucked offdry and after washing with absolute ether and absolute petroleum ether,it is dried in vacuum. The calcium salt of penicillin V is obtained in ayield of 7.5 g or 100% of theory, with an iodometrically determinedpurity of 92%.

EXAMPLE 13 A solution of 0.01 mole of the trimethylsilyl ester of6-(alpha-phenoxybutyramido) penicillanic acid is mixed with 10.8 ml of asolution of 0.005 mole of a calcium salt of 2-ethylhexanoic acid,dissolved in tetrahydrofuran, prepared as described in Example 1 1. Thesilyl ester is obtained by suspending the corresponding amount of thepotassium salt of penicillin in 50 ml absolute ether, mixing it with 1ml of N-methyl-N- trimethylsilylacetamide and 1.3 mltrimethylchlorosilane, and filtering under strict exclusion of airmoisture after allowing to stand for 2 hours. A precipitate is formedspontaneously which is sucked off. washed with ether and dried invacuum. The calcium salt of 6-(al pha-phenoxybutyramido)-penicillanicacid is obtained 13 in a yield of 3.7 g or 93 of theory, with aniodometrically determined purity of 96.5%.

EXAMPLE 14 A mixture of 6.5 g of APA, 75 ml of dry methylene chloride,and 4.1 ml of triethylamine is agitated at about C for 30 minutes andthen under agitation is slowly mixed with a solution of 1.83 ml of dichlorodimethylsilane in 15 ml of methylene chloride; the temperature isheld below 20C. The mixture is then agitated at room temperature for twomore hours. The mixture is then treated with a solution of 4.2 mltriethylamine in 15 ml methylene chloride and is cooled to C. At thattemperature a solution of 5.6 g alpha-phenoxypropionyl chloride in 50 mlof methylene chloride is added dropwise and it is then agitated furtherfor 90 minutes at 10 C. Upon the addition of 250 ml of dry petroleumether it is agitated for 10 minutes more and is then filtered underanhydrous conditions. To this solution there is added a solution of 5.5g potassium ethylhexanoate in 50 ml tetrahydrofuran is added (in acontrol experiment it has been ascertained that this solution stillcontained 0.316% water), whereby the precipitation of the potassium saltof penicillin began immediately. The latter was filtered off after somestanding. washed with methylene chloride and then with ether, and driedin vacuum. The yield is 7.4 g or 61.5% of theory; the iodometricallydetermined penicillin content is 97.5%. From the filtrate an additionalamount, 0.5 g or 4.2% of theory, of the penicillin salt accumulated uponmixing with ether.

EXAMPLE 15 6.5 g of APA is suspended in 65 ml of methylene chloride andmixed under agitation at 10-15C with 8.4 ml triethylamine and,subsequently, with 3.7 ml of dichlorodimethylsilane. The mixture, underagitation, is simmered for 2 hours under reflux, then cooled off andagitated for half an hour more at 510C. It is filtered under anhydrousconditions. The filtrate is treated with 4.2 ml of dryN.N-dimethylaniline and then, at 0C, under agitation, slowly, with asolution of 5.5 g of alpha-phenoxypropionyl chloride in 15 ml ofmethylene chloride. It is allowed to reach room temperature and isagitated at, this temperature for one more hour. It is then treated with250 m1 of dry petroleum ether and after agitation for 10 minutes, it isfiltered under anhydrous conditions. The filtrate is treated with asolution of 5.5 g of potassium ethylhexanoate in 50 ml oftetrahydrofuran and the potassium salt of penicillin formed is filteredoff after standing for two hours. After washing with methylene chlorideand ether it is dried in vacuum. The yield is 9.2 g or 76.1% of theory,with an iodometrically determined purity of 91%.

EXAMPLE 16 Following the procedure of the above example, and using 6 gof alpha-phenoxy-butyryl chloride, there is obtained the potassium saltof 6-(alpha-phenoxybutyrylamido)-penici1lanic acid in 82% yield oftheory.

EXAMPLE 17 3.41 g of anhydrous (l-aminocyclohexyl-l )-penicillin ismixed with 1.75 g of N-methyl-N-trimethylsilylacetamide and heated to4050C under agitation 14 till an, almost clear solution results. Uponcooling to room'temperature, it is mixed with 100 m1 anhydrous andalcohol-free acetic acid ethyl ester and the solution formed is freed ofthe very small amounts of undissolved substance by filtration.

A solution prepared from 0.4 g of sodium hydroxide and 1.44 g ofZ-ethylhexanoic acid in 20 ml of absolute tetrahydrofuran isconcentrated by evaporation in vacuum. The residue is dissolved in amixture of 5 ml of absolute tetrahydrofuran and ml of absolute ether andthe water content is then determined in an aliquot portion of thissolution. According to the Karl Fischer method the content of thesolution is 0.0081 mole of water., 1.5 gN-methyl-N-trimethylsilylacetamide is added for using up and binding thewater so determined. After about 10 minutes, the first prepared solutionof the silylated penicillin is quickly poured into the mixture obtained.The reaction mixture is kept at room temperature for two hours withoccasional shaking. Thereby, the sodium salt of the penicillin usedseparates out of Solution. It is sucked off under exclusion of moistureand is washed 3 times. each with 50 ml absolute ether. Finally. it isdried in vacuum at 5060C. The yield is 2.6 g or 72% of theory; theiodometrically determined penicillin is 94%.

EXAMPLE 18 The procedure of Example 17 is followed; however, the silylderivative of 1-aminocyclohexy1-l-penicillin is dissolved in 100 mlabsolute ether instead of acetic acid ethyl ester. In this manner, thesodium salt of penicillin is obtained in a yield of 3.2 g or 89% oftheory. with an iodometrically determined penicillin of 83%.

EXAMPLE 19 A suspension of 34.1 g of l-aminocyclohexyl-1- penicillin in500 ml absolute tetrahydrofuran is mixed under anhydrous conditions with28 ml of dry triethylamine and then slowly, with 26 ml oftrimethylchlorosilane. The reaction mixture is stirred for several hoursand the triethylamine hydrochloride formed is then removed by filtrationunder anhydrous conditions. The filtrate is concentrated to a volume ofabout 50 ml and is then treated with 500 ml absolute ether to giveSolution I.

A solution is prepared from 4.4 g of sodium hydroxide and 15.8 g of2-ethylhexanoic acid, dissolved in absolute tetrahydrofuran; it is thendried with sodium sulfate and concentrated by evaporation in vacuum. Theresidue yields after treatment with a mixture of 50 ml absolutetetrahydrofuran and 300 ml absolute ether, a solution which (accordingto a determination of its water content) contains 0.01 mole of water.Solution 1 is added to this solution and the reaction mixture is storedfor 1 hour. The precipitate is sucked off, washed 2 times, each with 200ml of ether, and then dried. Thus, the sodium salt ofl-aminocyclohexyl-1-penicillin is obtained in a yield of 37 g or 103% oftheory, with an iodometrically determined penicillin content of EXAMPLE20 43.2 g of APA is reacted, following the procedure of Example 3 A ofGerman Disclosure No. 1,800,698, in methylene chloride. to form thedisilyl derivative of APA by treating with 56.5 ml of triethylamine, and17 ml of pyridine (instead of the dimethylaniline used in the literaturereference mentioned), and 51 ml of trimethylchlorosilane. The solutionis then cooled and 39.7 g of the hydrochloride ofl-aminocyclohexane-lcarboxylic acid chloride are added portion-wiseunder good agitation; the temperature is kept at about 0C. Afterstirring for two hours (during which the mixture is allowed to assumeroom temperature), 600 ml of petroleum ether (boiling range 5060C isadded, and then the mixture is treated with 28 ml dry triethylamine. Themixture is stirred some more time, and it is then filtered underanhydrous conditions. The residue is washed with petroleum ether andthereafter the combined filtrates are separated from the main amount ofmethylene chloride in vacuum. Thus, a solution of the silylatedl-aminocyclohexyll-penicillin is obtained yielding Solution I.

A solution of 34 g of the sodium salt of 2-ethylhexanoic acid in 200 mlof absolute tetrahydrofuran and 100 ml absolute petroleum ether (whichwas prepared as in the preceding examples and contains a total of 574 gof water) is treated with Solution I under agitation. After 2 hours theprecipitate is sucked off dry and washed with ether. After drying at 80Cin vacuum. the sodium salt of l-aminocyclohexyl-l-penicillin is thusobtained in a yield of 73.8 g or 101.8% of theory. with aniodometrically determined penicillin content of 84%.

EXAMPLE 21 3.5 g of D(-)-alpha-aminobenzyl-penicillin are dis solved in1.75 g of N-methyl-N-trimethylsilylacetamide under agitation and heatingto 4050C. The solution is cooled to room temperature and treated with 50ml of absolute acetic acid ethyl ester. The clear solution obtained istreated with a dry solution of 1.7 g of the sodium salt of2-ethylhexanoic acid in acetic acid ethyl ester (which has been madeanhydrous by the addition of N-methyl-N-trimethylsilylacetamide). Aftersome time the precipitate is sucked off. washed with absolute ether. anddried in vacuum. The sodium salt of D(-)- alpha-aminobenzylpenicillin isobtained in a yield of 3.7 g or 100.9% of theory, with an iodometricallydetermined penicillin content of 92%.

EXAMPLE 22 7 g of D(-)-alpha-aminobenzylpenicillin are reacted with 3.5g of N-methyl-N-trimethylsilylacetamide. as in Example 21 and theproduct obtained is then dissolved in 100 ml of absolute ether. Thissolution is added to a dry solution of 0.02 mole of the potassium saltof 2- ethylhexanoic acid in ml absolute tetrahydrofuran. After one hourthe precipitate is sucked off. washed with absolute ether, and dried invacuum. Thus. the potassium salt of D(-)-alpha-aminobenzylpenicillin isobtained in a yield of 7.8 g and with an iodometrically determinedpenicillin content of 90 of theory.

EXAMPLE 23 3.41 g of l-aminocyclohexyl-1-penicillin is treated with 1.75g of N-methyl-N-trimethylsilylacetamide under agitation and heating to40 50C. After cooling to room temperature it is treated with 100 mlabsolute ether whereby a clear solution designated Solution 1. forms.

An anhydrous solution of 0.005 mole of the calcium salt of2-ethylhexanoic acid in 10 ml of tetrahydrofuran is treated withSolution 1. under agitation. A precipitate occurs spontaneously. Afterhalf an hour it is sucked off and washed 3 times, each with ml of ether.The

EXAMPLES 24 34 In the examples listed below the compound represented byR -O-Cat in that example as described above there is substituted thebelow-named reactant.

Examples Reactant 24 1 sodium salt of butyric acid 25 2 sodium salt ofdimethyl malonic acid 26 6 sodium salt of phenyl acetic acid 27 8calcium salt of alphaeth vl butyric acid 18 l 1 sodium salt of isoamylethyl acetic acid 29 12 sodium salt of isopropanol 30 I5 potassium saltof am \'l alcohol 31 17 sodium salt of tert. hutanol 32 19 sodium saltof ethanol 33 20 sodium salt of trimethyl silanol 34 potassium salt ofamyl alcohol The same salt product as described above in the respectiveexamples is obtained.

We claim:

1. 1n the process for preparing a sodium. potassium or calcium salt of apenicillin, a cephalosporin. a 6- amino-penicillanic acid. wherein thereis reacted a silyl derivative of the penicillin. the cephalosporin. orthe 6-aminopenicillanic acid in which derivative at least the carboxylgroup is linked. through the silicium atom. to a trimethylsilyl or adimethylsilyl group. the improvement which comprises using as a reactanta salt which is a member of the group consisting of a sodium. apotassium or a calcium salt of 2-ethylhexanoic acid. butyric acid.alpha-ethyl-butyric acid. isobutyric acid. dimethylmalonic acid. isoamylethyl acetic acid phenyl acetic acid, ethanol. of a propanol. a butanol.an amylalcohol, of phenol. trimethylsilanol or of triphenylsilanol, andforming said salt directly from said silyl derivative, withoutintermediate saponification of the ester to the free acid.

2. 1n the process of claim 1 for preparing a sodium. potassium orcalcium salt of a penicillin, selected from the group consisting ofalpha-phenoxy-acetyl-. alphaphenoxypropionyl-. alpha-phenoxybutyryl-.phenylacetyl-. alpha-amino phenyl acetyl-,l-amino-cyclohexan-1-carbonyl-. alpha-aminothienylacetyl-,alphaguanylureido-phenylacetylandalphacarboxythienylacetyl-6-amino-penicillanic acid. where there isreacted under anhydrous conditions. a silyl derivative of saidpenicillin in which derivative at least the carboxyl group is linkedthrough the silicium atom to a trimethylsilyl or a dimethylsilyl group.the improvement which comprises using as a reactant a salt which is amember of the group consisting of a sodium. a potassium or a calciumsalt of 2-ethylhexanoic acid, butyric acid, alpha-ethyl-butyric acid.isobutyric acid, dimethylmalonic acid. isoamyl ethyl acetic acid phenylacetic acid. ethanol. of a propanol. a butanol. an amylalcohol, ofphenol, trimethylsilanol or of triphenylsilanol and forming saidpenicillin salt directly from said silyl derivative.

17 3. The process of claim 1 wherein the silyl derivative is apenicillin. I

4. The process of claim 1 wherein the silyl derivative of thebeta-lactam ring-containingcarboxylic acid is a compound of the formulaZ 's CH... X- rL-CH-- {Cm o=c cooY wherein X is an acyl residue of acarboxylic acid of an alpha-amino. alpha-halogeno, or of analpha-loweralkoxy-phenylacetic acid, of a 3-(or 5-)aryl-5-( or3-)alkylisoxazolyl-4-carboxylic acid, or of al-amino-cyclohexane-l-carboxylic acid, Y is a group derived from atri-loweralkylor triphenyl silanol, or from a di-loweralkylor diphenylsilanol, wherein the lower alkyl is of l to 4 carbon atoms and is linkedwith a silicium atom. and Z is hydrogen or has the same definition as Y.

5. The process of claim 4 wherein the silyl derivative of thebeta-lactam ring-containing carboxylic acid is a compound in which atleast the carboxyl group is linked with a group of the formula wherein RR R is lower alkyl or phenyl.

6. The process of claim 1 wherein the compound R -O-Cat is an alkali oran alkaline earth salt of a fatty acid or of a di(lower alkyl)malonicacid.

7. The process of claim 1 wherein the reaction solution comprises asilylating reactant in an amount at least equivalent to the water orhydroxyl content of said solution.

8. The process of claim 7 wherein the silylating reactant is added priorto the reaction with the silyl derivative of the penicillin,cephalosporin or the 6-aminopenicillanic acid.

9. The process of claim 1 wherein the reaction is carried out in thepresence of an acyclic or cyclic ether, a saturated halogenatedhydrocarbon, an aromatic hydrocarbon or an ester of a carboxylic acidsolvent.

10. The process of claim 1 wherein the solution of the silyl derivativewhich is reacted is salt free.

11. The process of claim 10 which comprises preparing, prior to thereaction with the salt reactant, the salt-free solution of the silylderivative by treating a salt-containing solution of the silylatedpenicillin, cephalosporin or the 6-aminopenicillanic acid with a solventfor the silyl derivatives which is not a solvent for the salts, andremoving the salts.

12. The process of claim 1 wherein the silyl derivative has a pluralityof silyl groups and the reactant solution contains an amount of water orhydroxyl-containing solvent insufficient to desilylate the silylcompound.

13. The process of claim 1 wherein the silyl derivative product iswashed with a solvent which contains an amount of water orhydroxyl-containing solvent insufficient to complete the desilylation ofthe precipitated silyl salt derivative.

14. The process of claim 1 which comprises treating, prior to thereaction with the salt reactant. a silyl derivative of a 6-(aminoacylamido)-penicillanic acid having 18 a salt-like amino group toconvert said amino group to give the free and/or the silated compound.

15. The process of claim 1 which is carried out in the presence of anamount of water or other hydroxyl-containing solvent upto thatinsufficient to desilylate the silyl derivative of the carboxylic acid.

16. The process of claim 6 wherein the salt is a salt ofalpha-ethylhexanoic acid.

17. The process of claim 7 in which the silylaing reactant isN-methyl-N-trimethyl silylacetamide or trimethyl silylacetamide.

18. The process of claim 12 wherein the silyl derivative of the6-(aminoacylamido)-penicillanic acid is derived fromalpha-aminobenzyl-penicillin or from l-aminocyclohexyl-l )-penicillin.

19. The process of claim 4 wherein the aryl in 3-(or 5-)aryl-5-( or3-)alkylisoxazolyl-4-carboxylic acid is phenyl or loweralkyl phenyl.

20. The process of claim 4 wherein the two reactants are broughttogether at a temperature in the range between the freezing point to theboiling point of the reaction mixture.

21. The process of claim 20 wherein the temperature is 50 to 50C.

22. The process of claim 21 wherein the temperature is in the range of 5to about 35C.

23. The process of claim 22 wherein the temperature is in the range ofabout 20 to 30C.

24. The process of claim 4 wherein the two reactants are used insubstantially equimolar amount.

25. The process of claim 4 wherein the salt reactant is used in anamount in the range of about 1 to 1.1.

26. The process of claim 4 wherein the salt which is formed is isolatedthereafter from the reaction mixture.

27. The process for preparing a salt of a penicillin which comprisesbringing together and reacting, in the presence of an aprotonic organicsolvent a silyl derivative of a penicillin of the formula the samedefinition as Y, with a compound of the formula R O Cat wherein R is anacyl residue derived from a carboxylic acid which is free of protonicgroups, or an alkyl, an aryl residue or a group of the formula wherein Rto R, is alkyl or aryl and wherein Cat is a cation, and forming saidsalt directly from said silyl derivative.

28. The process of claim 27 wherein X is the acyl residue of analpha-amino, alpha-halogeno, or of an alphaloweralkylphenoxy aceticacid, of a 3-aryl-5- alkyl-isoxazolyl-4-carboxylic acid, or of al-aminocyclohexanel -carboxylic acid.

29. In the process for preparing a salt of a carboxylic acid containinga beta-lactam ring wherein the silyl derivative is a compound of theformula wherein X is an acyl residue of a carboxylic acid of up to 4carbon atoms; of an alpha-amino. alpha-halogeno. or of analpha-lower-alkoxy-phenylacetic acid. of a 3-(or 5-) aryl-5-(or 3-)alkyl-isoxazolyl-4-carboxylic acid, or ofal-aminocyclohexane-l-carboxylic acid. Y is a group derived from atri-lower-alkylor triphenylsilanol. or from a di-loweralkyl ordi-phenylsilandiol wherein R to R is lower alkyl or phenyl and whereinCat is calcium. potassium or sodium. and forming the salt directly fromsaid silyl derivative without intermediate saponification of the esterto the free acid.

1. IN THE PROCESS FOR PREPARING A SODIUM, POTASSIUM OR CALCIUM SALT OF APENICILLIN, A CEPHALOSPORIN, A 6-AMINOPENICILLANIC ACID, WHEREIN THEREIS REACTED A SILYL DERIVATIVE OF THE PENICILLIN, THE CEPHALOSPORIN, ORTHE 6-AMINOPENICILLANIC ACID IN WHICH DERIVATIVE AT LEAST THE CARBOXYLGROUP IS LINKED, THROUGH THE SILICIUM ATOM, TO A TRIMETHYLSILYL OR ADIMETHYLSILYL GROUP, THE IMPROVEMENT WHICH COMPRISES USING AS A REACTANTA SALT WHICH IS A MEMBER OF THE GROUP CONSISTING OF A SODIUM, APOTASSIUM OR A CALCIUM SALT OF 2-ETHYL-HEXANOIC ACID, BUTYRIC ACID,ALPHA-ETHYL-BUTYRIC ACID, ISOBUTYRIC ACID, DIMETHYLMALONIC ACID, ISOAMYLETHYL ACETIC ACID PHENYL ACETIC ACID, ETHANOL, OF A PROPANOL, A BUTANOL,AN AMYLALCOHOL, OF PHENOL, TRIMETHYLSILANOL OR OF TRIPHENYLSILANOL, ANDFORMING SAID SALT DIRECTLY FROM SAID SILYL DERIVATIVE, WITHOUTINTERMEDIATE SAPONIFICATION OF THE ESTER OF THE FREE ACID.
 2. IN THEPROCESS OF CLAIM 1 OF PREPARING A SODIUM, POTASSIUM OR CALCIUM SALT OF APENICILLIN, SELECTED FROM THE GROUP CONSISTING OF ALPHA-PHENOXY-ACETYL-,ALPHA-PHENOXYPROPIONYL, ALPHA-PHENOXYBUTYRYL-, PHENYLACETYL-,ALPHA-AMINO PHENYL ACETYL-, 1-AMINO-CYCLOHEXAN-1-CARBONYL-,ALPHA-AMINOTHIENYLACETYL-, ALPHA-GUANYLUREIDO-PHENYLACETYL- ANDALPHACARBOXY-THIENYLACETYL-6-AMINO-PENICILLANIC ACID, WHERE THERE ISREACTED UNDER ANHYDROUS CONDITIONS, A SILYL DERIVATIVE OF SAIDPENICILLIN IN WHICH DERIVATIVE AT LEAST THE CARBOXYL GROUP IS LINKEDTHROUGH THE SILICIUM ATOM TO A TRIMETHYLSILYL OR A DIMETHYLSILYL GROUP,THE IMPROVEMENT WHICH COMPRISES USING AS A REACTANT A SALT WHICH IS AMEMBER OF THE GROUP CONSISTING OF A SODIUM, A POTASSIUM OR A CALCIUMSALT OF 2-ETHYLHEXANOIC ACID, BUTYRIC ACID, ALPHA-ETHYL-BUTYRIC ACID,SIOBUTYRIC ACID, DIMETHYLMALONIC ACID, ISOAMYL ETHYL ACETIC ACID PHENYLACETIC ACID, ETHANOL, OF A PROPANOL, A BUTANOL, AN AMYLALCOHOL, OFPHENOL, TRIMETHYLSILANOL OR OF TRIPHENYLSILANOL AND FORMING SAIDPENICILLIN SALT DIRECTLY FROM SAID SILYL DERIVATIVE.
 3. The process ofclaim 1 wherein the silyl derivative is a penicillin.
 4. The process ofclaim 1 wherein the silyl derivative of the beta-lactam ring-containingcarboxylic acid is a compound of the formula
 5. The process of claim 4wherein the silyl derivative of the beta-lactam ring-containingcarboxylic acid is a compound in which at least the carboxyl group islinked with a group of the formula
 6. The process of claim 1 wherein thecompound R1-O-Cat is an alkali - or an alkaline earth salt of a fattyacid or of a di(lower alkyl)malonic acid.
 7. The process of claim 1wherein the reaction solution comprises a silylating reactant in anamount at least equivalent to the water or hydroxyl content of saidsolution.
 8. The process of claim 7 wherein the silylating reactant isadded prior to the reaction with the silyl derivative of the penicillin,cephalosporin or the 6-amino-penicillanic acid.
 9. The process of claim1 wherein the reaction is carried out in the presence of an acyclic orcyclic ether, a saturated halogenated hydrocarbon, an aromatichydrocarbon or an ester of a carboxylic acid solvent.
 10. The process ofclaim 1 wherein the solution of the silyl derivative which is reacted issalt free.
 11. The process of claim 10 which compriSes preparing, priorto the reaction with the salt reactant, the salt-free solution of thesilyl derivative by treating a salt-containing solution of the silylatedpenicillin, cephalosporin or the 6-aminopenicillanic acid with a solventfor the silyl derivatives which is not a solvent for the salts, andremoving the salts.
 12. The process of claim 1 wherein the silylderivative has a plurality of silyl groups and the reactant solutioncontains an amount of water or hydroxyl-containing solvent insufficientto desilylate the silyl compound.
 13. The process of claim 1 wherein thesilyl derivative product is washed with a solvent which contains anamount of water or hydroxyl-containing solvent insufficient to completethe desilylation of the precipitated silyl salt derivative.
 14. Theprocess of claim 1 which comprises treating, prior to the reaction withthe salt reactant, a silyl derivative of a6-(aminoacylamido)-penicillanic acid having a salt-like amino group toconvert said amino group to give the free and/or the silated compound.15. The process of claim 1 which is carried out in the presence of anamount of water or other hydroxyl-containing solvent up to thatinsufficient to desilylate the silyl derivative of the carboxylic acid.16. The process of claim 6 wherein the salt is a salt ofalpha-ethylhexanoic acid.
 17. The process of claim 7 in which thesilylaing reactant is N-methyl-N-trimethyl silylacetamide or trimethylsilylacetamide.
 18. The process of claim 12 wherein the silyl derivativeof the 6-(aminoacylamido)-penicillanic acid is derived fromalpha-aminobenzyl-penicillin or from (1-aminocyclohexyl-1)-penicillin.19. The process of claim 4 wherein the aryl in 3-(or 5-)aryl-5-(or3-)alkylisoxazolyl-4-carboxylic acid is phenyl or loweralkyl phenyl. 20.The process of claim 4 wherein the two reactants are brought together ata temperature in the range between the freezing point to the boilingpoint of the reaction mixture.
 21. The process of claim 20 wherein thetemperature is -50* to 50*C.
 22. The process of claim 21 wherein thetemperature is in the range of -5* to about 35*C.
 23. The process ofclaim 22 wherein the temperature is in the range of about 20* to 30*C.24. The process of claim 4 wherein the two reactants are used insubstantially equimolar amount.
 25. The process of claim 4 wherein thesalt reactant is used in an amount in the range of about 1 to 1.1. 26.The process of claim 4 wherein the salt which is formed is isolatedthereafter from the reaction mixture.
 27. The process for preparing asalt of a penicillin which comprises bringing together and reacting, inthe presence of an aprotonic organic solvent a silyl derivative of apenicillin of the formula
 28. The process of claim 27 wherein X is theacyl residue of an alpha-amino, alpha-halogeno, or of analphaloweralkylphenoxy acetic acid, of a3-aryl-5-alkyl-isoxazolyl-4-carboxyLic acid, or of a1-amino-cyclohexane-1-carboxylic acid.
 29. In the process for preparinga salt of a carboxylic acid containing a beta-lactam ring wherein thesilyl derivative is a compound of the formula